Drug interaction of thalidomide with midazolam and other compounds : heterotropic cooperativiy of human cyochrome P450

• Project/Area Number: 21590177
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: MURAYAMA Norie 昭和薬科大学, 薬学部, 講師 (90219949)
• Co-Investigator(Kenkyū-buntansha): YAMAZAKI Hiroshi 昭和薬科大学, 薬学部, 教授 (30191274) ; SHIMIZU Makiko 昭和薬科大学, 薬学部, 助教 (90307075)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 薬物相互作用 / サリドマイド / 協同性 / ヒト型モデルマウス / P450 / HepaRG / チトクロムP450 / CYP3A4 / GSH / CYP3A / 促進定数 / ミダゾラム水酸化活性

Research Abstract

There is growing clinical interest of thalidomide because of its immunomodulatory and antiangiogenic properties, despite its teratogenicity. However, little information about thalidomide has been reported regarding its precise effects on drug-metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450(P450) enzymes in human liver microsomes to clarify the potential for possible drug interactions. The present results suggest that total midazolam metabolism or cyclosporine A clearance may be increased by thalidomide in a dose-dependent manner. Unexpected drug interactions involving thalidomide might occur via heterotropic cooperativity of polymorphic P450 3A5.We investigate these drug interactions in cultured human liver cell line system more closely resembled livers. A new hepatic cell line system with differentiated HepaRG cryopreserved(Biopredic International, Rennes, France) was adopted. These results suggest that cultured human cell line system with differentiated HepaRG cryopreserved could be applicable to thalidomide drug interaction study. Further oxidative metabolism of 5-hydoroxythalidomide to 5-hydroxythalidomide GSH-conjugate formation is under investigation using the new HepaRG cell system mimicking in vivo human livers.

Research Products

• [Journal Article] Evaluation of drug toxicity with hepatocytes cultured in a micro-space cell culture system (2011)
  • Author(s): Nakamura, K., Mizutani, R., Sanbe, A., Enosawa, S., Kasahara, M., Nakagawa, A., Ejiri, Y., Murayama, N., Miyamoto, Y., Torii, T., Kusakawa, S., Yamauchi, J., Fukuda, M., Yamazaki, H., and Tanoue. A
  • Journal Title: J. Biosci. Bioeng Volume: 111 Pages: 78-84
  • NAID: 110008440354
  • Peer Reviewed
• [Journal Article] Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants (2011)
  • Author(s): Akiyoshi, T. Saito, T., Murase, S., Miyazaki, M. Murayama, N., Yamazaki, H., Guengerich, F. P., Nakamura, K., Yamamoto, K., and Ohtani, H
  • Journal Title: Drug Metab. Dispos Volume: 39 Issue: 4 Pages: 724-728
  • DOI: 10.1124/dmd.110.036780
  • Peer Reviewed
• [Journal Article] Species d ifference between cynomolgus monkeys and humans on cytochromes P450 2D and 3A-dependent drug oxidation activities in liver microsomes (2011)
  • Author(s): Emoto, C., Iwasaki, K., Koizumi, R., Utoh, M., Murayama, N., Uno Y., and Yamazaki, H
  • Journal Title: J. Health Sci Volume: 57 Pages: 164-170
  • NAID: 130000663115
  • URL: http://dx.doi.org/10.1248/jhs.57.164
  • Peer Reviewed
• [Journal Article] Sorafenib and sunitinib, two anti-cancer drugs, inhibit CYP3A4-and activate CYP3A5-mediated midazolam 1' hydroxylation (2011)
  • Author(s): Sugiyama, M., Fujita, K., Murayama, N., Akiyama, Y., Yamazaki, H., and Sasaki, Y
  • Journal Title: Drug Metab. Dispos Volume: 39 Issue: 5 Pages: 757-762
  • DOI: 10.1124/dmd.110.037853
  • Peer Reviewed
• [Journal Article] Human liver enzymes responsible for metabolic elimination of tyramine, a vasopressor agent from daily food (2011)
  • Author(s): Niwa, T., Murayama, N., Umeyama, H., Shimizu, M., and Yamazaki, H
  • Journal Title: Drug Metab. Lett Volume: 5 Pages: 216-219
  • Peer Reviewed
• [Journal Article] Individual differences in pharmacokinetics and pharmacodynamics of anesthetic agent propofol with regard to CYP2B6 and UGT1A9 genotype and patient age (2011)
  • Author(s): Kansaku F, Kumai T, Sasaki K, Yokozuka M, Shimizu M, Tateda T, Murayama N, Kobayashi S, Yamazaki H
  • Journal Title: Drug Metab Pharmacokinet Volume: 26 Pages: 532-7
  • NAID: 130004463217
  • URL: http://dx.doi.org/10.2133/dmpk.DMPK-11-RG-039
  • Peer Reviewed
• [Journal Article] Stereoselectivity of human cytochrome p450 in metabolic and inhibitory activities (2011)
  • Author(s): Niwa T, Murayama N, Yamazaki H
  • Journal Title: Curr Drug Metab Volume: 12 Pages: 549-69
  • Peer Reviewed
• [Journal Article] Comparison of cytochrome P450 2D6 and variants in terms of drug oxidation rates and substrate inhibition (2011)
  • Author(s): Niwa T, Murayama N, Yamazaki H
  • Journal Title: Curr Drug Metab Volume: 12 Pages: 412-35
  • Peer Reviewed
• [Journal Article] CYP2G2, pseudogenized in human, is expressed in nasal mucosa of cynomolgus monkey and encodes a functional drug-metabolizing (2011)
  • Author(s): Uno Y, Uehara, S., Murayama, N., Yamazaki, H.
  • Journal Title: Drug Metab.Dispos. Volume: 39 Issue: 4 Pages: 717-723
  • DOI: 10.1124/dmd.110.036574
  • Peer Reviewed
• [Journal Article] Mechanism-based inhibition of cytochrome P450 (CYP) 2A6 by chalepensin in recombinant systems, in human liver microsomes and mice in vivo (2011)
  • Author(s): Ueng, Y.-F., Chen, C.-C., Chung, Y.-T, Liu, T.-Y., Chang, Y.-P., Lo, W.-S., Murayama, N., Yamazaki, H., Soucek, P., Chau, G.-Y., Chi, C.-W., Chen, R.-M., Li D.T.
  • Journal Title: Brit.J.Pharmacol. Volume: 163 Issue: 6 Pages: 1250-1262
  • DOI: 10.1111/j.1476-5381.2011.01341.x
  • Peer Reviewed
• [Journal Article] In Vivo Formation of a Glutathione Conjugate Derived from Thalidomide in Humanized uPA-NOG (2011)
  • Author(s): Yamazaki, H., Suemizu, H.(8名・2番目)
  • Journal Title: Mice Chem Res Toxicol Volume: 24 Issue: 3 Pages: 287-289
  • DOI: 10.1021/tx200005g
  • Peer Reviewed
• [Journal Article] Human liver enzymes responsible for metabolic elimination of tyramine, a vasopressor agent from daily food (2011)
  • Author(s): Niwa, T., Murayama, N., Umeyama, H., Shimizu, M., Yamazaki, H.
  • Journal Title: Drug Metab.Lett Volume: 5 Pages: 216-219
  • Peer Reviewed
• [Journal Article] Individual Differences in Pharmacokinetics and Pharmacodynamics of Anesthetic Agent Propofol with Regard to CYP2B6 and UGT1A9 Genotype and Patient Age (2011)
  • Author(s): Kansaku, F, Kumai, T., Sasaki, K., Yukozuka, M., Shimizu, M., Tateda, T., Murayama, N., Kobayashi, S., Yamazaki, H.
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 26 Issue: 5 Pages: 532-537
  • DOI: 10.2133/dmpk.DMPK-11-RG-039
  • NAID: 130004463217
  • ISSN: 1347-4367, 1880-0920
  • Peer Reviewed
• [Journal Article] Immunochemical detection of cytoclirome P450 enzymes in liver microsomes of 27 cynomolgus monkeys (2011)
  • Author(s): Uehara, S., Murayama, N., Nakanishi, Y., Zeldin, D.C., Yamazaki, H., Uno, Y.
  • Journal Title: J.Pharmacol.Exp.Ther Volume: 339 Issue: 2 Pages: 654-661
  • DOI: 10.1124/jpet.111.185009
  • Peer Reviewed
• [Journal Article] Species difference between cynomolgus monkeys and humans on cytochromes P450 2D and 3A-dependent drug oxidation activities in liver microsomes. (2011)
  • Author(s): Emoto, C., Iwasaki, K., Koizumi, R., Utoh, M., Murayama, N., Uno Y., Yamazaki, H.
  • Journal Title: J.Health Sci. Volume: 57 Pages: 164-170
  • NAID: 130000663115
  • Peer Reviewed
• [Journal Article] Evaluation of drug toxicity with hepatocytes cultured in a micro-space cell culture system. (2011)
  • Author(s): Nakamura, K., Mizutani, R., Sanbe, A., Enosawa, S., Kasahara, M., Nakagawa, A., Ejiri, Y., Murayama, N., Miyamoto, Y., Torii, T., Kusakawa, S., Yamauchi, J., Fukuda, M., Yamazaki, H., Tanoue.A.
  • Journal Title: J.Biosci.Bioeng Volume: 111 Pages: 78-84
  • NAID: 110008440354
  • Peer Reviewed
• [Journal Article] Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants. (2011)
  • Author(s): Akiyoshi, T.Saito, T., Murase, S., Miyazaki, M.Murayama, N.Yamazaki, H., Guengerich, F.P., Nakamura, K., Yamamoto, K., Ohtani, H
  • Journal Title: Drug Metab.Dispos. Volume: 39 Pages: 74-728
  • Peer Reviewed
• [Journal Article] Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate (2010)
  • Author(s): Chowdhury, G., Murayama, N., Okada, Y., Uno, Y., Shimizu, M., Shibata, N., Guengerich, F. P., and Yamazaki, H
  • Journal Title: Chem. Res. Toxicol Volume: 23 Pages: 1018-1024
  • Peer Reviewed
• [Journal Article] Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling (2010)
  • Author(s): Takano R, Murayama N, Horiuchi K, Kitajima M, Kumamoto M, Shono F, Yamazaki H
  • Journal Title: Regul Toxicol Pharmacol Volume: 58 Pages: 252-8
  • Peer Reviewed
• [Journal Article] Structure-function relationships of inhibition of human cytochromes P450 1A1, 1A2, 1B1, 2C9, and 3A4 by 33 flavonoid derivatives (2010)
  • Author(s): Shimada, T., Tanaka, K., Takenaka, T., Murayama, N., Martin, M. V., Foroozesh, M. K. Yamazaki, H., Guengerich, F. P, and Komori. M
  • Journal Title: Chem. Res. Toxicol. Volume: 23 Issue: 12 Pages: 1921-1935
  • DOI: 10.1021/tx100286d
  • NAID: 130004639911
  • Peer Reviewed
• [Journal Article] Human liver microsomal cytochrome P450 3A enzymes involved in thalidomide 5-hydroxylation and formation of a glutathione conjugate. (2010)
  • Author(s): Chowdhury, G.., Murayama, N., Okada, Y., Uno, Y., Shimizu, M., Shibata, N., Guengerich, F.P., Yamazaki, H.
  • Journal Title: Chem.Res.Toxicol. Volume: 23 Pages: 1018-1024
  • Peer Reviewed
• [Journal Article] Blood concentrations of 1, 4-dioxane in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling. (2010)
  • Author(s): Takano, R., Murayama, N., Horiuchi, K., Kitajima, M., Shono F., Yamazaki, H..
  • Journal Title: J.Health Sci. Volume: 56 Pages: 557-565
  • NAID: 130000425091
  • Peer Reviewed
• [Journal Article] In vivo formation of a glutathione conjugate derived from thalidomide in humanized uPA-NOG mice. (2010)
  • Author(s): Yamazaki, H., Suemizu, H., Igaya, S., Shimizu, M., Shibata, N., Nakamura, M., Chowdhury, G., Guengerich, F.P.
  • Journal Title: Chem.Res.ToxicoL Volume: 24 Pages: 287-289
  • Peer Reviewed
• [Journal Article] Comparison of cytochrome P450 3A enzymes in cynomolgus monkeys and humans (2010)
  • Author(s): Iwasaki, K., Murayama, N., Koizumi, R., Uno, Y., Yamazaki, H.
  • Journal Title: Drug Metab.Pharmacokinet. (印刷中)
  • NAID: 10027583437
  • Peer Reviewed
• [Journal Article] Utilization of estimated physicochemical properties as an integrated part of predicting hepatic clearance in the early drug discovery stage : The impact of plasma and microsomal binding (2009)
  • Author(s): Emoto, C., Murayama, N.Rostami-Hodjegan, A., Yamazaki, H.
  • Journal Title: Xenobiotica 39 Pages: 227-235
  • Peer Reviewed
• [Journal Article] Cytochrome P450-dependent drug oxidation activity of liver microsomes from Microminipigs, a possible new animal model for humans in non-clinical studies (2009)
  • Author(s): Murayama, N., Kaneko, N., Horiuchi, K., Ohyama, K., Shimizu, M., Ito, K., Yamazaki, H
  • Journal Title: Drug Metab.Pharmacokinet. 24 Pages: 404-408
  • Peer Reviewed
• [Journal Article] Reverse type I binding spectra of human cytochrome P450 1B1 induced by flavonoid, stilbene, pyrene, naphthalene, phenanthrene, and biphenyl derivatives that inhibit catalytic activity : A structure-function relationship study (2009)
  • Author(s): Shimada, T., Tanaka, K.Takenaka, S.Foroozesh, M.K., Murayama, N., Yamazaki, H., Guengerich, F.P., Komori, M.Murayama, N., Kaneko, N., Horiuchi, K., Ohyama, K., Shimizu, M., Ito, K., Yamazaki, H
  • Journal Title: Chem.Res.Toxicol. 22 Pages: 1325-1333
  • Peer Reviewed
• [Journal Article] Effects of histidine-tag on recombinant human cytochrome P450 3A5 catalytic activity in reconstitution systems (2009)
  • Author(s): Emoto, C., Murayama, N., Wakiya, S., Yamazaki, H.
  • Journal Title: Drug Metab.Lett.t. 3 Pages: 207-211
  • Peer Reviewed
• [Journal Article] Oxidation of endobiotics mediated by xenobiotic-metabolizing forms of human cytochrome P450 (2009)
  • Author(s): Niwa, T., Murayama, N., Yamazaki, H.
  • Journal Title: Curr.Drug Metab. 10 Pages: 700-712
  • Peer Reviewed
• [Presentation] チオカルバメート系除草剤モリネートの代謝消失における種差の検討 (2012)
  • Author(s): 村山典恵、山下真直、塚田藍、末水洋志、中村雅登、高野良治、清水万紀子、山崎浩史
  • Organizer: 日本薬学会第132回年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] チオカルバメート系除草剤モリネートの代謝消失における種差の検討 (2012)
  • Author(s): 村山典恵、山下真直、塚田藍、高野良治、末水洋志、中村雅登、清水万紀子、山崎浩史
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 札幌市・北海道大学・高等教育推進機構
  • Year and Date: 2012-03-28
• [Presentation] Drug Metabolism In Human Hepatoma Cell Line System with Differentiated HepaRG Cryopresorved (2011)
  • Author(s): Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, Hiroshi Yamazaki
  • Organizer: JSSX
  • Place of Presentation: 広島市・国際会議場
  • Year and Date: 2011-11-22
• [Presentation] Drug metabolism in human hepatomacell line system with differentiated HepaRG cryopreserved (2011)
  • Author(s): Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, and Hiroshi Yamazaki
  • Organizer: 26th JSSX Annual Meeting
  • Place of Presentation: 広島
  • Year and Date: 2011-11-17
• [Presentation] Drug interactions of thalidomide with midazolam in human hepatoma cell line system with differentiated HepaRG cryopreserved (2011)
  • Author(s): Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, and Hiroshi Yamazaki
  • Organizer: 17 th North American regional ISSX meeting
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2011-10-18
• [Presentation] Drug Interaction of Thalidomide with Midazolam in Human Hepatoma Cell Line System with Differentiated HepaRG Cryopreserved (2011)
  • Author(s): Norie Murayama, Kanako Yajima, Makiko Shimizu, Masahiro Utoh, Hiroshi Yamazaki
  • Organizer: 17^<th> Notth America ISSX Meeting
  • Place of Presentation: Atranta, USA, Hotel Hirtone
  • Year and Date: 2011-10-17
• [Presentation] 肝試料画分を考慮した化学物質のヒト生理学的薬物動態モデルの精緻化 (2011)
  • Author(s): 村山典恵、國兼絵里子、塚田藍、高野良治、北島正人、清水万紀子、池田敏彦、山崎浩史
  • Organizer: 日本薬学会第131回年会
  • Place of Presentation: 静岡
  • Year and Date: 2011-03-29
• [Presentation] 肝試料画分を考慮した化学物質のヒト生理学的薬物動態モデルの精緻化 (2011)
  • Author(s): 村山典恵、國兼絵里子、塚田藍、高野良治、北島正人、清水万紀子、山崎浩史
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 要旨集上にて発表
  • Year and Date: 2011-03-05
• [Presentation] An improved method to assess internal radiation exposure in humans using in vivo and in vitro animal pharmacokinetic data (2010)
  • Author(s): Toshihiko Ikeda, Norie Murayama and Hiroshi Yamazaki
  • Organizer: 25th JSSX Annual Meeting
  • Place of Presentation: 埼玉
  • Year and Date: 2010-10-08
• [Presentation] Individual differences in pharmacokinetics and pharmacodynamics of anesthetic agent propofol in patients genotyped for CYP2B6 and UGT1A9 (2010)
  • Author(s): Hiroshi Yamazaki, Toshio Kumai, Kuniharu Sasaki, Makito Yokozuka, Makiko Shimizu, Tadashi Tateda, Norie Murayama and Shinichi Kobayashi
  • Organizer: ISSX Workshop on Genetic Polymorphisms in Drug Disposition
  • Place of Presentation: Indianapolis, USA
  • Year and Date: 2010-04-11
• [Presentation] ヒトと実験動物間で認められる薬物代謝酵素機能の種差 (2010)
  • Author(s): 村山典恵, 今村裕樹, 大久保真穂, 國兼絵里子, 松本史彦, 小野瀬優維, 佐々木国玄, 清水万紀子, 山崎浩史
  • Organizer: 日本薬学会第130回総会
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-29
• [Presentation] Impact of genetic polymorphism of the CYP3A5 appeared in the metabolism of and inhibition by voriconazoke in a Japanese population (2009)
  • Author(s): 村山典恵, 清水万紀子, 山崎浩史
  • Organizer: 日本薬物動態学会
  • Place of Presentation: 京都
  • Year and Date: 2009-11-27
• [Presentation] Impact of cytochrome p450 3A5 expression in human livers on drug interactions of anti-fungal agents with midazolam (2009)
  • Author(s): 村山典恵, 中本美那子, 清水万紀子, 山崎浩史
  • Organizer: 16th International Conference on Cytochrome P450 ～Biochemistry, Biophysics, Biotechnology～
  • Place of Presentation: 沖縄
  • Year and Date: 2009-06-21
• [Presentation] Remarked properties of human cytochrome P450 1A2 and 3A5 in function and cooperativity for drug development (2009)
  • Author(s): 山崎浩史
  • Organizer: 16th International Conference on Cytochrome P450 ～Biochemistry, Biophysics, Biotechnology～
  • Place of Presentation: 沖縄
  • Year and Date: 2009-06-21
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